We thank Funda&#231;&#227;o de Amparo &#224; Pesquisa do Estado de S&#227;o Paulo (FAPESP, S&#227;o Paulo, Brazil) for financial support (Grant FAPESP 2017/18400-6). This study was financed in part by the Coordena&#231;&#227;o de Aperfei&#231;oamento de Pessoal de N&#237;vel Superior &#8211; Brasil (CAPES) &#8211; Finance Code 001.

CAUTION: Consult Material Safety Data Sheets (MSDS) prior to the use of the chemicals in this procedure. Use appropriate personal protective equipment (PPE), including safety glasses, a lab coat, and nitrile gloves as several reagents and solvents are toxic, corrosive, or flammable. Carry out all reactions in a fume hood. Liquids used in this protocol are micropipette transferred.
1. Benzannulation reaction employing alkynes and &#945;,&#946;-unsaturated compounds
<ol>
	<li>Add 2.0 mL of distilled water to a 15 mL-test tube (1 cm diameter) containing a stir bar. Sequentially, add phenylacetylene (220 &#956;L, 2.00 mmol, 2.0 equiv.), 2-cyclohexen-1-one (96.8 &#956;L, 1.00 mmol, 1.0 equiv.) and ammonium persulfate (1.5 mL of a freshly prepared aqueous solution 1.3 M, 2.00 mmol, 2 equiv.).</li>
	<li>Cap the tube using a rubber septum and insert a needle in it to avoid eventual pressure buildup during the heating.</li>
	<li>Place the tube in an aluminum heating block on a hotplate and heat it at 85 &#176;C under vigorous stirring (1150 rpm) for 8 h.</li>
	<li>To follow the progress of the reaction, take a 50 &#956;L-aliquot of the reaction medium and transfer it to a 1.5 mL-conical vial. Add 50 &#956;L of ethyl acetate to the vial and shake it. Collect the organic top layer with a capillary tube and analyze it by TLC. 
	NOTE: Reaction progress is checked by TLC comparing the disappearance of the &#945;,&#946;-unsaturated compound spot to the appearance of the product under the UV light (254 nm). TLC analysis is performed with silica-coated glass plates and developed with 92:8 hexanes/ethyl acetate. Rf values: phenylacetylene = 0.68; 2-cyclohexen-1-one = 0.23; product 3e = 0.26. 
	CAUTION: Phenylacetylene and 2-cyclohexen-1-one are flammable, acutely toxic and mild irritants. Ammonium persulfate is corrosive and may irritate the mucous membranes.</li>
</ol>
2. Extraction workup and purification
<ol>
	<li>Cool the reaction mixture to room temperature and add ethyl acetate (1 mL) to the test tube. Stir the suspension for ca. 1 min and then centrifuge the suspension at 2,336 &#215; g at room temperature for 1 min. Remove the organic top layer using a Pasteur pipette and transfer it to a round bottom flask. Repeat this step twice. 
	NOTE: The centrifugation step avoids the use of drying agents and readily breaks any eventual emulsion.</li>
	<li>Concentrate the solution under reduced pressure using a rotary evaporator to obtain a crude oil.</li>
	<li>Add 55 mL of a mixture of hexanes/ethyl acetate at the ratio of 92:8 into a Becker containing 7.5 g of SiO2 (pore size 60 &#197;, 35-70 &#956;m particle size, for flash chromatography). Stir the flask to obtain a homogeneous slurry. Transfer the slurry to a column (40 mm internal diameter) and pack the column eluting the solvent. If necessary, elute once again to remove any bubbles from the stationary phase.</li>
	<li>Dissolve the crude oil in a minimal amount of ethyl acetate, and then transfer this solution to the column. Using the same 55 mL of a mixture 92:8 hexanes/ethyl acetate, elute the material, collecting the column effluent in test tubes and following by TLC to obtain the desired pure product.</li>
	<li>Concentrate the solution under reduced pressure on a rotary evaporator and remove the final volatiles under high vacuum for at least 1 h. Analyze a sample of the purified product by 1H and 13C NMR using CDCl3. 
	CAUTION: Ethyl acetate and hexanes are flammable. SiO2 powder is a respiratory irritant.</li>
</ol>

<ol>
	<li>Colacot, T. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> New Trends in Cross-Coupling. Theory and Applications. , (2015).</li><li>Hassan, J., S&#233;vignon, M., Gozzi, C., Schulz, E., Lemaire, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Aryl-Aryl+Bond+Formation+One+Century+after+the+Discovery+of+the+Ullmann+Reaction.">Aryl-Aryl Bond Formation One Century after the Discovery of the Ullmann Reaction.</a> Chemical Reviews. 102 (5), 1359 (2002).</li><li>Snieckus, V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Directed+Aromatic+Functionalization+and+references+therein.">Directed Aromatic Functionalization and references therein.</a> Beilstein Journal of Organic Chemistry. 7, 1215-1218 (2011).</li><li>Ashenhurst, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intermolecular+oxidative+cross-coupling+of+arenes.">Intermolecular oxidative cross-coupling of arenes.</a> Chemical Society Reviews. 39 (2), 540-548 (2010).</li><li>Reich, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Role+of+Organolithium+Aggregates+and+Mixed+Aggregates+in+Organolithium+Mechanisms.">Role of Organolithium Aggregates and Mixed Aggregates in Organolithium Mechanisms.</a> Chemical Reviews. 113 (9), 7130-7178 (2013).</li><li>van Otterlo, W. A. L., de Koning, C. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Metathesis+in+the+Synthesis+of+Aromatic+Compounds.">Metathesis in the Synthesis of Aromatic Compounds.</a> Chemical Reviews. 109, 3743-3782 (2009).</li><li>Zhou, P., Huang, L. B., Jiang, H. F., Wang, A. Z., Li, X. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Highly+Chemoselective+Palladium-Catalyzed+Cross-Trimerization+between+Alkyne+and+Alkenes+Leading+to+1,3,5-Trienes+or+1,2,4,5-Tetrasubstituted+Benzenes+with+Dioxygen.">Highly Chemoselective Palladium-Catalyzed Cross-Trimerization between Alkyne and Alkenes Leading to 1,3,5-Trienes or 1,2,4,5-Tetrasubstituted Benzenes with Dioxygen.</a> Journal of Organic Chemistry. 75, 8279-8282 (2010).</li><li>Li, S., Wu, X. X., Chen, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Base-promoted+direct+synthesis+of+functionalized+N-arylindoles+via+the+cascade+reactions+of+allenic+ketones+with+indoles.">Base-promoted direct synthesis of functionalized N-arylindoles via the cascade reactions of allenic ketones with indoles.</a> Organic and Biomolecular Chemistry. 17, 789-793 (2019).</li><li>Maezono, S. M. B., Poudel, T. N., Lee, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=One-pot+construction+of+sterically+challenging+and+diverse+polyarylphenols+via+transition-metal-free+benzannulation+and+their+potent+in+vitro+antioxidant+activity.">One-pot construction of sterically challenging and diverse polyarylphenols via transition-metal-free benzannulation and their potent in vitro antioxidant activity.</a> Organic and Biomolecular Chemistry. 15, 2052-2062 (2017).</li><li>Shu, W. M., Zheng, K. L., Ma, J. R., Wu, A. X. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transition-Metal-Free+Multicomponent+Benzannulation+Reactions+for+the+Construction+of+Polysubstituted+Benzene+Derivatives.">Transition-Metal-Free Multicomponent Benzannulation Reactions for the Construction of Polysubstituted Benzene Derivatives.</a> Organic Letters. 17, 5216-5219 (2015).</li><li>Jiang, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Secondary+amine-catalyzed+[3+benzannulation+to+access+polysubstituted+benzenes+through+iminium+activation.">Secondary amine-catalyzed [3 benzannulation to access polysubstituted benzenes through iminium activation.</a> Synthetic Communications. 48, 336-343 (2018).</li><li>Koening, S. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Scalable Green Chemistry. Case Studies from the Pharmaceutical Industry. , (2013).</li><li>Backvall, J. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Modern Oxidation Methods. , (2004).</li><li>Narayan, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term="On+Water":+Unique+Reactivity+of+Organic+Compounds+in+Aqueous+Suspension.">"On Water": Unique Reactivity of Organic Compounds in Aqueous Suspension.</a> Angewandte Chemie International Edition. 44, 3275-3277 (2005).</li><li>de Souza, G. F. P., Salles, A. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Persulfate-Mediated+Synthesis+of+Polyfunctionalized+Benzenes+in+Water+via+Benzannulation+of+Alkynes+and+&#945;,&#946;-Unsaturated+Compounds.">Persulfate-Mediated Synthesis of Polyfunctionalized Benzenes in Water via Benzannulation of Alkynes and &#945;,&#946;-Unsaturated Compounds.</a> Green Chemistry. , (2019).</li><li>Prat, D., Wells, A., Hayler, J., Sneddon, H., McElroy, C. R., Abou-Shehada, S., Dunn, P. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=CHEM21+Selection+Guide+of+Classical-+and+Less+Classical-Solvents.">CHEM21 Selection Guide of Classical- and Less Classical-Solvents.</a> Green Chemistry. 18, 288-296 (2015).</li><li>Sheldon, R. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Metrics+of+Green+Chemistry+and+Sustainability:+Past,+Present,+and+Future.">Metrics of Green Chemistry and Sustainability: Past, Present, and Future.</a> ACS Sustainable Chemistry &amp; Engineering. 6, 32-48 (2018).</li></ol>

The authors have nothing to disclose.

The method reported herein was designed to be a very simple and mild experimental setup for the synthesis of polyfunctionalized benzenes in water15. Under our conditions we could observe excellent yields for the products through the use of ammonium persulfate. A freshly prepared persulfate aqueous solution should be used; however, solid ammonium persulfate can also be employed with no loss in yield. Attention to the temperature of the reaction medium is mandatory. An increase in 10 &#176;C beyond ...

Functionalized benzenes are arguably the most employed precursors in synthetic organic chemistry1,2. They figure in the mainstream of pharmaceuticals, natural products and functional organic materials. Powerful approaches have been reported for the construction of polysubstituted benzene derivatives and among them, well-established methods as aromatic nucleophilic or electrophilic substitution3, cross-coupling reactions4 and directed metalation5 are prevalent approaches. Nevertheless, the widespread application of these strategies may be hampered by limited substrate scope, overreaction and regioselectivity issues.
Tandem cyclization reactions represent a very attractive alternative to classical methods for rapid construction of functionalized benzenes in an atom-economical fashion6,7,8. Within this framework, benzannulation reactions represent a suitable protocol to effectively transform acyclic building blocks into valuable benzene skeletons. This class of reaction is a versatile methodology featuring a variety of chemical feedstocks, mechanisms and experimental conditions9,10,11.
The objective of our study is to develop a simple and practical protocol for a benzannulation reaction to generate unprecedented functionalized benzene rings. Toward this end, we set out to explore a metal-free, persulfate mediated benzannulation in water employing cheap chemical feedstocks (&#945;,&#946;-unsaturated compounds and alkynes).
Several advantages over methods reported in the literature can be pointed out. Metal-free transformations have all necessary attributes to meet the requirement of sustainable development. Just to mention few, there is no need for costly and challenging removal of metal trace amounts from the desired products; the reactions are less sensitive to oxygen and moisture making its manipulation easier and the overall process is normally less expensive12. Persulfate salts are stable, easy to handle and generate only sulphate as the byproduct, thus adding momentum to the green chemistry initiative to minimize waste pollution13. Water is considered a suitable green solvent for organic reactions: it is non-toxic, non-flammable, has a very low odor and is available at a low cost. Even water-insoluble organic compounds can be employed using "on water"14 aqueous suspensions and these straightforward synthetic protocols have been gaining increasing attention during the years.
Our optimized reaction conditions and simple workup/purification procedure provide access to several functionalized benzene rings that offer a wealth of opportunities for further functionalization.

<table><tbody><tr><td>Ammonium persulfate</td><td>Vetec</td><td>276</td><td></td></tr><tr><td>Chloroform-D, (D, 99.8%)</td><td>Sigma Aldrich</td><td>570699-50G</td><td></td></tr><tr><td>2-cyclohexen-1-one &gt;95%</td><td>Sigma Aldrich</td><td>C102814-25ML</td><td></td></tr><tr><td>Ethyl Acetate, 99.9%</td><td>Synth</td><td>01A1010.01.BJ</td><td>ACS</td></tr><tr><td>Hexanes, 98.5%</td><td>Synth</td><td>01H1007.01.BJ</td><td>ACS</td></tr><tr><td>Phenylacetylene 98%</td><td>Sigma Aldrich</td><td>117706-25ML</td><td></td></tr><tr><td>Silica Gel (SiO&lt;sub&gt;2&lt;/sub&gt;)</td><td>Fluka</td><td>60738-5KG</td><td>pore size 60 &amp;Aring;, 35-70 &amp;mu;m particle size</td></tr><tr><td>Thin-layer chromatography plates</td><td>Macherey-Nagel</td><td>818333</td><td>0.20 mm silica gel 60 with fluorescent indicator UV254</td></tr></tbody></table>

efficient synthesis of polyfunctionalized benzenes in water via persulfate-promoted benzannulation of &#945;,&#946;-unsaturated compounds and alkynes

Benzannulation reactions represent an effective protocol to transform acyclic building blocks into structurally varied benzene skeletons. Despite classical and recent approaches toward functionalized benzenes, in water metal-free methods remains a challenge and represents an opportunity to expand even more the set of tools used to synthesize polysubstituted benzene compounds. This protocol describes an operationally simple experimental setup to explore the benzannulation of &#945;,&#946;-unsaturated compounds and alkynes to afford unprecedented functionalized benzene rings in high yields. Ammonium persulfate is the reagent of choice and brings notable advantages as stability and easy handling. Moreover, the use of water as a solvent and the absence of metals impart more sustainability to the method. A modified workup procedure that avoids the use of drying agents also adds convenience to the protocol. The purification of the products is performed using only a plug of silica. The substrate scope is currently limited to terminal alkynes and &#945;,&#946;-unsaturated aliphatic compounds.

Polysubstituted benzene (3b, Figure 1) was isolated as a colorless oil (0.2741 g, 0.920 mmol, 92% yield) using our protocol. The structure and purity can be assessed in the 1H and 13C NMR spectra presented in Figure 2 and Figure 3. Peaks for the aromatic protons on the central benzene ring (&#948; 8.37 and &#948; 7.72 ppm) were used as diagnostic signals for the formation of the product.
<p...

Watch this Scientific Journal Video about Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of Î±,Î²-Unsaturated Compounds and Alkynes at JoVE.com

Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of &#945;,&#946;-Unsaturated Compounds and Alkynes

A persulfate-promoted metal-free benzannulation of &#945;,&#946;-unsaturated compounds and alkynes in water toward the synthesis of unprecedented polyfunctionalized benzenes is reported.

Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of &#945;,&#946;-Unsaturated Compounds and Alkynes

Benzannulation reactions represent an effective protocol to transform acyclic building blocks into structurally varied benzene skeletons. Despite ...

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Reactions of Aromatic Compounds

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7.7K Views.  University of Campinas. A persulfate-promoted metal-free benzannulation of α,β-unsaturated compounds and alkynes in water toward the synthesis of unprecedented polyfunctionalized benzenes is reported.

Video: Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of α,β-Unsaturated Compounds and Alkynes

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the preparation of all-carbon quaternary centers. Though conjugate additions of organometallic reagents are typically performed utilizing highly reactive organolithium or Grignard reagents, organozinc reagents have garnered attention for their enhanced chemoselectivity and mild reactivity. Despite numerous recent advances with more reactive diorganozinc and mixed diorganozinc reagents, the generation of all-carbon quaternary centers via the conjugate addition of functionalized monoorganozinc reagents remains a challenge. This protocol details a convenient and mild &#8220;one-pot&#8221; preparation and copper mediated conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to afford a broad scope of all-carbon quaternary centers in generally excellent yield and diastereoselectivity. Key to the development of this technology is the utilization of DMA as a reaction solvent with TMSCl as a Lewis acid. Notable advantages to this methodology include the operational simplicity of the organozinc reagent preparation afforded by the utilization of DMA as a solvent, as well as an efficient conjugate addition mediated by various Cu(I) and Cu(II) salts. Moreover, an intermediate silyl enol ether can be isolated utilizing a modified workup procedure. The substrate scope is limited to cyclic unsaturated ketones, and the conjugate addition is impeded by stabilized (e.g., allyl, enolate, homoenolate) and sterically encumbered (e.g., neopentyl, o-aryl) monoorganozinc reagents. Conjugate additions to five- and seven-membered rings were effective, albeit in lower yields compared with six-membered ring substrates.

A simple and practical protocol for the efficient conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to furnish all-carbon quaternary centers was developed.

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the ...

Easy Access to Aliphatic Sulfonamides using Sulfamoyl Chlorides Under Visible Light Activation

Sulfonamides are prevalent motifs in marketed drugs and natural products. Their synthesis represents a great interest to the pharmaceutical industry, due to their unique biological properties. Recently, several methods for the synthesis of aryl sulfonamides have been developed, but little effort has focused on developing one-step methodologies to access sulfonamides flanked by two alkyl groups. This protocol describes a practical and facile method for the net hydrosulfamoylation of electron-deficient alkenes using sulfamoyl chlorides as radical precursors under blue-light activation. This practical and cost-effective methodology is performed in the presence of the metal-free photocatalyst Eosin Y and uses light as a clean and traceless energy source. The procedure is scalable, displays a broad functional group tolerance, and can be applied for late-stage functionalization. All reagents used in this protocol are commercially available. Simple reaction set-up, the absence of work-up and easy purification, demonstrate the convenience of this protocol. The reaction is best applied to electron-deficient alkenes.

Presented here is a protocol for the easy synthesis of aliphatic sulfonamides using sulfamoyl chlorides, (TMS)3SiH and Eosin Y under blue-light irradiation.

Sulfonamides are prevalent motifs in marketed drugs and natural products. Their synthesis represents a great interest to the pharmaceutical industry, due ...

Synthesis of a Borylated Ibuprofen Derivative Through Suzuki Cross-Coupling and Alkene Boracarboxylation Reactions

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drugs used to manage and treat pain and inflammation. In 2016, a new class of boron functionalized NSAIDs (bora-NSAIDs) was synthesized under mild conditions via the copper-catalyzed regioselective boracarboxylation of vinyl arenes using carbon dioxide (CO2 balloon) and a diboron reductant at room temperature. This original method was performed primarily in a glovebox or with a vacuum gas manifold (Schlenk line) under rigorous air-free and moisture-free conditions, which often led to irreproducible reaction outcomes due to trace impurities. The present protocol describes a simpler and more convenient benchtop method for synthesizing a representative bora-NSAID, bora-ibuprofen. A Suzuki-Miyaura cross-coupling reaction between 1-bromo-4-isobutylbenzene and vinylboronic acid pinacol ester produces 4-isobutylstyrene. The styrene is subsequently boracarboxylated regioselectively to provide bora-ibuprofen, an &#945;-aryl-&#946;-boryl-propionic acid, with good yield on a multi-gram scale. This procedure allows for the broader utilization of copper-catalyzed boracarboxylation in synthetic laboratories, enabling further research on bora-NSAIDs and other unique boron-functionalized drug-like molecules.

The present protocol describes a detailed benchtop catalytic method that yields a unique borylated derivative of ibuprofen.&#160;

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drugs used to manage and treat pain and inflammation. In 2016, a new class of ...

Reactions at the Benzylic Position: Halogenation

Benzylic halogenation takes place under conditions that favor radical reactions such as heat, light, or a free radical initiator like peroxide.
<img alt="Figure1" src="/files/ftp_upload/12873/12873_PT_Figure_1.svg" style="text-align: center; height: 165px;" />
The reaction of toluene with an excess of chlorine can produce multiple benzylic chlorinations. However, the reaction of N-bromosuccinimide or NBS with toluene in the presence of a peroxide forms benzyl bromide. Halogenation of larger alkyl side chains are highly regioselective and occur primarily at the benzylic position. Bromination of ethylbenzene at the benzylic position solely gives a monobromo organic product. Whereas chlorination of ethylbenzene gives 1-chloro-1-phenylethane as the major product in the ratio of 9:1. The regioselectivity of halogenation reaction can be explained by the resonance stabilization of the benzylic radical intermediate. Benzylic halogenation is important because halogen substituted at the benzylic position can further be replaced by a different group.
<img alt="Figure2" src="/files/ftp_upload/12873/12873_PT_Figure_2.svg" style="text-align: center; height: 60px;" />

Benzylic halogenation takes place under conditions that favor radical reactions such as heat, light, or a free radical initiator like peroxide.

The ...

KEY TERMS AND CONCEPTS

Preparation of Alcohols via Addition Reactions

<h4>Overview</h4>
The acid-catalyzed addition of water to the double bond of alkenes is a large-scale industrial method used to synthesize low-molecular-weight alcohols. An acidic atmosphere is required to allow the hydrogen in the water molecule to act as an electrophile and attack the double bond in an alkene. The addition of a proton to the double bond creates a carbocation intermediate. The proton preferentially bonds to the less substituted end of the double bond to create a more stable carbocation intermediate. Subsequently, water attacks the carbocation to yield a&#160; protonated alcohol.
Here, the reaction is regioselective and prefers Markovnikov&#39;s addition of water to the alkene. The proton is added to the less substituted end of the double bond, and the -OH group is added to the more substituted carbon on the other end. The reaction is not stereoselective since the water can approach the planar carbocation from both sides, which leads to a racemic mixture of alcohols. Water addition can happen from the same side (syn addition) or the opposite side (anti addition) with respect to the direction from which the proton is added to the double bond. In alkenes with a more substituted carbon adjacent to the double bond, the positive charge in the carbocation intermediate may rearrange (1,2 hydride shift or 1,2 methyl shift) to gain stability. In this situation, a mixture of constitutional isomers of alcohols is formed as products.
An alternative synthetic route for preparing alcohols from alkenes is via oxymercuration-demercuration reaction. In the oxymercuration reaction, the electrophilic mercury in mercury acetate is added to the double bond and forms a three-membered ring structure called mercurinium ion. Water then attacks the mercurinium ion to form organomercurial alcohol. The subsequent step is demercuration, where sodium borohydride replaces the mercury species with hydrogen.
The hydroxyl group bound to the more substituted carbon in the mercurinium ion guides the hydrogen towards the less substituted carbon, eventually resulting in a Markovnikov&#39;s product. Also, attack by water is anti with respect to mercury acetate addition. However, the reaction that replaces mercury species with hydrogen is not stereoselective, which results in the formation of both enantiomers of the alcohol as the final product. Due to the absence of a conventional carbocation and its rearrangement, oxymercuration-demercuration has better yields than direct acid-catalyzed hydration.
Anti-Markovnikov&#39;s addition of water to an alkene can be performed by the hydroboration-oxidation method. Hydroboration is the single-step addition of a B-H bond from a borane to the two carbons in the double bond via a four-membered transition state. Electrophilic boron attracts the &#960; orbital electrons from the least hindered carbon in the double bond. The resulting partial positive charge is stabilized on the other more substituted carbon atom. Steric factors also favor the addition of boron to the least hindered carbon and hydrogen to the other. The alkyl borane intermediate further reacts with two more alkene molecules to yield a trialkyl borane intermediate. Oxidation of trialkyl borane with hydrogen peroxide in sodium hydroxide replaces the boron with a hydroxyl group. The simultaneous addition of boron and hydrogen from borane ensures a syn addition over the double bond. However, the syn addition can happen from either face of the alkene.
Due to the difference in regiochemistry and reaction mechanisms, these three different synthetic pathways result in different alcohols from the same alkene substrate, as shown in
<img alt="Figure1" src="/files/ftp_upload/11923/11923Figure_1.svg" style="text-align: center; height: 200px;" />
Figure 1. Addition of water over 3,3-dimethyl-1butene under acid-catalysis (top),&#160; oxymercuration-demercuration (middle) and hydroboration-oxidation conditions (bottom).&#160;

Overview
The acid-catalyzed addition of water to the double bond of alkenes is a large-scale industrial method used to synthesize low-molecular-weight ...

Alcohols and Phenols

Electrophilic Aromatic Substitution: Chlorination and Bromination of Benzene

Chlorination and bromination are important classes of electrophilic aromatic substitutions, where benzene reacts with chlorine or bromine in the presence of a Lewis acid catalyst to give halogenated substitution products. A Lewis acid such as aluminium chloride or ferric chloride catalyzes the chlorination, and ferric bromide catalyzes the bromination reactions. During the bromination of alkenes, bromine polarizes and becomes electrophilic. However, in the bromination of benzene, the bromine molecule reacts with ferric bromide by donating a pair of electrons to the Lewis acid, which creates a more polar Br&#8211;Br bond and forming a more reactive electrophile.
<img alt="Figure1" src="/files/ftp_upload/12874/12874_PT_Figure_1.svg" style="text-align: center; height: 36px;" />
The benzene attacks this electrophile to generate the arenium ion, which is resonance stabilized.
<img alt="Figure2" src="/files/ftp_upload/12874/12874_PT_Figure_2.svg" style="text-align: center; height: 70px;" />
A proton transfer from arenium ion forms bromobenzene, thereby restoring aromaticity and regenerating the catalyst.
<img alt="Figure3" src="/files/ftp_upload/12874/12874_PT_Figure_3.svg" style="text-align: center; height: 75px;" />
The mechanism of chlorination of benzene proceeds in the same manner as bromination of benzene.

Chlorination and bromination are important classes of electrophilic aromatic substitutions, where benzene reacts with chlorine or bromine in the presence ...

Electrophilic Aromatic Substitution: Nitration of Benzene

The nitration of benzene is an example of an electrophilic aromatic substitution reaction. It involves the formation of a very powerful electrophile, the nitronium ion, which is linear in shape. The reaction occurs through the interaction of two strong acids, sulfuric and nitric acid.
<img alt="Figure1" src="/files/ftp_upload/12465/12465_Figure_1.svg" style="text-align: center; height: 45px;" />
Sulfuric acid is stronger and protonates the nitric acid on the hydroxyl group, followed by loss of water molecule, generating the nitronium ion.
<img alt="Figure2" src="/files/ftp_upload/12465/12465_Figure_2.svg" style="text-align: center; height: 100px;" />
The nitronium ion acts as an electrophile that reacts with benzene to form a resonance-stabilized arenium ion. The arenium ion then loses its proton to a Lewis base forming nitrobenzene.
<img alt="Figure3" src="/files/ftp_upload/12465/12465_Figure_3.svg" style="text-align: center; height: 175px;" />
 The resulting nitro group can be reduced to a primary amino group. Reduction is achieved either by hydrogenation with a transition metal catalyst such as nickel, palladium, or platinum under mild conditions or upon treatment with metals in aqueous acid. Iron, zinc, and tin in dilute HCl are widely used reducing agents. However, ammonium ion is obtained as a salt under acidic conditions, which is then treated with a base such as sodium hydroxide to liberate the free amine.

The nitration of benzene is an example of an electrophilic aromatic substitution reaction. It involves the formation of a very powerful electrophile, the ...

Electrophilic Aromatic Substitution: Sulfonation of Benzene

Sulfonation of benzene is a reaction wherein benzene is treated with fuming sulfuric acid at room temperature to produce benzenesulfonic acid. Fuming sulfuric acid is a mixture of sulfur trioxide and concentrated sulfuric acid.
<img alt="Figure1" src="/files/ftp_upload/12466/12466_Figure_1.svg" style="text-align: center; height: 45px;" />
The active electrophile is either neutral sulfur trioxide or protonated sulfur trioxide ion, depending on the reaction conditions. One of the mechanisms involves neutral sulfur trioxide acting as an electrophile, which reacts with the &#960; electron cloud of nucleophilic benzene, forming a resonance stabilized intermediate. Further, the loss of a proton from the intermediate restores its aromaticity. Finally, proton transfer from the solvent leads to the formation of benzenesulfonic acid.
<img alt="Figure2" src="/files/ftp_upload/12466/12466_Figure_2.svg" style="text-align: center; height: 275px;" />
The other mechanism involves protonated sulfur trioxide ion as the electrophile, generated upon activation of sulfur trioxide through proton transfer from sulfuric acid.
<img alt="Figure3" src="/files/ftp_upload/12466/12466_Figure_3.svg" style="text-align: center; height: 90px;" />
As an electrophile, the protonated ion attacks with the &#960; electron cloud of benzene, forming an arenium ion.
<img alt="Figure4" src="/files/ftp_upload/12466/12466_Figure_4.svg" style="text-align: center; height: 100px;" />
Finally, deprotonation of the arenium ion restores aromaticity, providing the benzenesulfonic acid as the final product and regenerating the acid catalyst.
<img alt="Figure5" src="/files/ftp_upload/12466/12466_Figure_5v2.svg" style="text-align: center; height: 110px;" />
Dilute sulfuric acid and steam can reverse the sulfonation reaction.
<img alt="Figure6" src="/files/ftp_upload/12466/12466_Figure_6.svg" style="text-align: center; height: 110px;" />
Aromatic sulfonation is widely used in the synthesis of detergents, dyes, and sulfa drugs.

Sulfonation of benzene is a reaction wherein benzene is treated with fuming sulfuric acid at room temperature to produce benzenesulfonic acid. Fuming ...

Alkynes to Aldehydes and Ketones: Hydroboration-Oxidation

<h4>Introduction</h4>
One of the convenient methods for the preparation of aldehydes and ketones is via hydration of alkynes. Hydroboration-oxidation of alkynes is an indirect hydration reaction in which an alkyne is treated with borane followed by oxidation with alkaline peroxide to form an enol that rapidly converts into an aldehyde or a ketone. Terminal alkynes form aldehydes, whereas internal alkynes give ketones as the final product.
<img alt="Figure1" src="/files/ftp_upload/11839/11839_PT_Figure_1.svg" style="text-align: center; height: 200px;" />
<h4>Mechanism</h4>
The hydroboration-oxidation reaction is a two-step process. It begins with the hydroboration step, which involves a concerted syn addition of BH3 across the carbon&#8211;carbon triple bond to form an alkenylborane. The concerted nature of the reaction also accounts for the anti-Markovnikov regiochemistry, where the BH2 group adds to the less substituted carbon and H to the more substituted carbon of the triple bond.
<img alt="Figure2" src="/files/ftp_upload/11839/11839_PT_Figure_2.svg" style="text-align: center; height: 120px;" />
&#160;Three successive hydroboration reactions convert an alkene into a trialkenylborane intermediate. The second part of the sequence is oxidation, where the trialkenylborane is treated with alkaline hydrogen peroxide to form an enol. The enol eventually converts into a stable carbonyl product via keto-enol tautomerism.
<img alt="Figure3" src="/files/ftp_upload/11839/11839_PT_Figure_3.svg" style="text-align: center; height: 250px;" />
<h4>Hydroboration of Alkynes with Disubstituted Boranes</h4>
Unlike alkenes, hydroboration of alkynes does not stop at the first addition of BH3. This is because alkynes have two &#960; bonds, each capable of reacting with BH3. The first addition forms an organoborane, which is an alkene derivative that can react further with another equivalent of BH3.
Terminal alkynes being less hindered than internal alkynes are more susceptible to a second BH3 addition. With internal alkynes, the addition of BH3 stops after the first stage and proceeds in a direction to give the trialkenylborane.
<img alt="Figure4" src="/files/ftp_upload/11839/11839_PT_Figure_4.svg" style="text-align: center; height: 250px;" />
&#160;Nevertheless, hydroboration of terminal alkynes can be stopped at the first step by using bulky disubstituted boranes (R2BH) such as disiamylborane and 9-BBN instead of BH3.
<img alt="Figure5" src="/files/ftp_upload/11839/11839_PT_Figure_5.svg" style="text-align: center; height: 130px;" />
The first addition of the bulky reagent forms a sterically hindered alkenylborane that resists any further additions and helps in the efficient conversion of alkynes to stable carbonyl compounds.
<img alt="Figure6" src="/files/ftp_upload/11839/11839_PT_Figure_6.svg" style="text-align: center; height: 100px;" />

Hydroboration-Oxidation of Alkynes to Aldehydes and Ketones

Introduction
One of the convenient methods for the preparation of aldehydes and ketones is via hydration of alkynes. Hydroboration-oxidation of alkynes is ...

Alkynes

Nucleophilic Aromatic Substitution: Elimination&ndash;Addition

Simple aryl halides do not react with nucleophiles. However, nucleophilic aromatic substitutions can be&#160;forced under&#160;certain conditions, such as high temperatures or strong bases. The mechanism of substitution under such conditions involves the highly unstable and reactive benzyne intermediate. Benzyne contains equivalent carbon centers at both ends of the triple bond, each of which&#160;is equally susceptible to nucleophilic attack. This 50&#8211;50 distribution of products is confirmed through isotopic labeling. The overall mechanism follows an elimination&#8211;addition pathway. A strong base generates a carbanionic center on the ring. Next, elimination of the halide produces the benzyne intermediate, which is&#160;highly strained&#160;and therefore extremely reactive at both ends of the triple bond. Addition of the nucleophile at either end gives the product with 50&#8211;50 distribution.

Nucleophilic Aromatic Substitution: Elimination&amp;#8211;Addition

Simple aryl halides do not react with nucleophiles. However, nucleophilic aromatic substitutions can be&#160;forced under&#160;certain conditions, such as ...

Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of α,β-Unsaturated Compounds and Alkynes

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